complement factor i

Summary

Summary: A plasma serine proteinase that cleaves the alpha-chains of C3b and C4b in the presence of the cofactors COMPLEMENT FACTOR H and C4-binding protein, respectively. It is a 66-kDa glycoprotein that converts C3b to inactivated C3b (iC3b) followed by the release of two fragments, C3c (150-kDa) and C3dg (41-kDa). It was formerly called KAF, C3bINF, or enzyme 3b inactivator.

Top Publications

  1. Kavanagh D, Kemp E, Mayland E, Winney R, Duffield J, Warwick G, et al. Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16:2150-5 pubmed
    ..Both of these proteins act as co-factors for complement factor I (IF)...
  2. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006;108:1267-79 pubmed
    ..Hopefully this will translate into improved management and therapy of patients and will provide the way to design tailored treatments...
  3. Ullman C, Haris P, Smith K, Sim R, Emery V, Perkins S. Beta-sheet secondary structure of an LDL receptor domain from complement factor I by consensus structure predictions and spectroscopy. FEBS Lett. 1995;371:199-203 pubmed
    ..Sequence threading against known protein folds indicated consistency with small beta-sheet proteins. Complement factor I contains two LDLrs, and the second of these was successfully expressed using a bacterial pGEX system...
  4. Roversi P, Johnson S, Caesar J, McLean F, Leath K, Tsiftsoglou S, et al. Structural basis for complement factor I control and its disease-associated sequence polymorphisms. Proc Natl Acad Sci U S A. 2011;108:12839-44 pubmed publisher
    ..In addition to explaining how circulating fI is limited to cleaving only C3b/C4b, our model explains the molecular basis of disease-associated polymorphisms in fI and its cofactors. ..
  5. Shiang R, Murray J, Morton C, Buetow K, Wasmuth J, Olney A, et al. Mapping of the human complement factor I gene to 4q25. Genomics. 1989;4:82-6 pubmed
    A detailed genetic and physical map of human complement factor I (IF) using somatic cell hybrids, in situ hybridization, and genetic linkage is reported. The gene has been localized to band 4q25...
  6. Tsiftsoglou S, Sim R. Human complement factor I does not require cofactors for cleavage of synthetic substrates. J Immunol. 2004;173:367-75 pubmed
    b>Complement factor I (fI) plays a major role in the regulation of the complement system...
  7. Nilsson S, Karpman D, Vaziri Sani F, Kristoffersson A, Salomon R, Provot F, et al. A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation. Mol Immunol. 2007;44:1835-44 pubmed
    ..In conclusion, despite the association between the heterozygous mutation in FI and aHUS we did not observe any abnormalities in the function of FI regarding complement regulation. ..
  8. Delvaeye M, Noris M, De Vriese A, Esmon C, Esmon N, Ferrell G, et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:345-57 pubmed publisher
    ..Mutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic-uremic syndrome. ..
  9. Reynolds R, Hartnett M, Atkinson J, Giclas P, Rosner B, Seddon J. Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes. Invest Ophthalmol Vis Sci. 2009;50:5818-27 pubmed publisher
    ..C5a is associated with AMD genotypes. C statistics are stronger with the addition of C3a, Bb, and C5a in predictive models. Results implicate ongoing activation of the alternative complement pathway in AMD pathogenesis. ..

More Information

Publications62

  1. Minta J, Fung M, Paramaswara B. Transcriptional and post-transcriptional regulation of complement factor I (CFI) gene expression in Hep G2 cells by interleukin-6. Biochim Biophys Acta. 1998;1442:286-95 pubmed
    We have investigated the effects of IL-1 and IL-6 on human complement factor I (CFI) production by Hep G2 cells. IL-6 treatment caused a dose- and time-dependent increase in CFI secretion while IL-1 did not demonstrate such effects...
  2. Abernathy J, Lu J, Liu H, Kucuktas H, Liu Z. Molecular characterization of complement factor I reveals constitutive expression in channel catfish. Fish Shellfish Immunol. 2009;27:529-34 pubmed publisher
    ..Complement is tightly regulated by a group of both soluble and cell-associated proteins. Complement factor I is a soluble serine protease that regulates multiple pathways in complement activation...
  3. Hair P, Echague C, Sholl A, Watkins J, Geoghegan J, Foster T, et al. Clumping factor A interaction with complement factor I increases C3b cleavage on the bacterial surface of Staphylococcus aureus and decreases complement-mediated phagocytosis. Infect Immun. 2010;78:1717-27 pubmed publisher
    ..High levels of factor I binding by clinical strains correlated with poor phagocytosis. In summary, our results suggest that the interaction of ClfA with factor I contributes to S. aureus virulence by a complement-mediated mechanism. ..
  4. Nilsson S, Trouw L, Renault N, Miteva M, Genel F, Zelazko M, et al. Genetic, molecular and functional analyses of complement factor I deficiency. Eur J Immunol. 2009;39:310-23 pubmed publisher
    ..This is the first study that investigates, at the functional level, the consequences of molecular defects identified in patients with full FI deficiency. ..
  5. Liu W, Liu B, Xin L, Zhang Y, Chen X, Zhu Z, et al. Down-regulated expression of complement factor I: a potential suppressive protein for gastric cancer identified by serum proteome analysis. Clin Chim Acta. 2007;377:119-26 pubmed
    ..There were 3 proteins including complement C4-B precursor, complement factor I (CFI) precursor and haptoglobin precursor were found significantly different between the healthy and ..
  6. Schlaf G, Demberg T, Beisel N, Schieferdecker H, Gotze O. Expression and regulation of complement factors H and I in rat and human cells: some critical notes. Mol Immunol. 2001;38:231-9 pubmed
    ..These data support the notion that FI in contrast to FH is not expressed by cells of the monocyte-macrophage lineage or by other leukocytes of peripheral blood, at least in the absence of additional stimulants. ..
  7. Geelen J, van den Dries K, Roos A, van de Kar N, de Kat Angelino C, Klasen I, et al. A missense mutation in factor I (IF) predisposes to atypical haemolytic uraemic syndrome. Pediatr Nephrol. 2007;22:371-5 pubmed
    ..One additional transplant was lost due to arterial thrombosis of the renal artery. This report confirms the gloomy outcome of renal transplants in patients with an IF deficiency. New therapies should be evaluated in these patients...
  8. Tsiftsoglou S, Arnold J, Roversi P, Crispin M, Radcliffe C, Lea S, et al. Human complement factor I glycosylation: structural and functional characterisation of the N-linked oligosaccharides. Biochim Biophys Acta. 2006;1764:1757-66 pubmed
  9. Goldberger G, Bruns G, Rits M, Edge M, Kwiatkowski D. Human complement factor I: analysis of cDNA-derived primary structure and assignment of its gene to chromosome 4. J Biol Chem. 1987;262:10065-71 pubmed
    ..By exclusion, this defines as cellular the basis for the inefficient processing of pro-I by the HepG2 line. Chromosomal localization by the somatic cell hybrid method maps the factor I gene to chromosome 4. ..
  10. Grumach A, Leitão M, Arruk V, Kirschfink M, Condino Neto A. Recurrent infections in partial complement factor I deficiency: evaluation of three generations of a Brazilian family. Clin Exp Immunol. 2006;143:297-304 pubmed
    ..Vaccination against capsulated bacteria and the eventual use of prophylactic antibiotics should be considered individually in this patient group. ..
  11. Nilsson S, Kalchishkova N, Trouw L, Fremeaux Bacchi V, Villoutreix B, Blom A. Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I. Eur J Immunol. 2010;40:172-85 pubmed publisher
    ..All 14 complement factor I mutations associated with aHUS analyzed in this study were heterozygous and generated premature stop codons ..
  12. Fremeaux Bacchi V, Dragon Durey M, Blouin J, Vigneau C, Kuypers D, Boudailliez B, et al. Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet. 2004;41:e84 pubmed
  13. Timár K, Junnikkala S, Dallos A, Jarva H, Bhuiyan Z, Meri S, et al. Human keratinocytes produce the complement inhibitor factor I: Synthesis is regulated by interferon-gamma. Mol Immunol. 2007;44:2943-9 pubmed
    ..Factor I produced by keratinocytes was functionally active in cleaving C3b. In conclusion, we demonstrate that keratinocytes are capable of synthesizing factor I, and that this synthesis is regulated by IFN-gamma. ..
  14. Miyake M, Yamashiro K, Nakanishi H, Nakata I, Akagi Kurashige Y, Kumagai K, et al. Evaluation of pigment epithelium-derived factor and complement factor I polymorphisms as a cause of choroidal neovascularization in highly myopic eyes. Invest Ophthalmol Vis Sci. 2013;54:4208-12 pubmed publisher
    ..A case-control study in a relatively large cohort of highly myopic patients was conducted to explore the genetic background of the occurrence of choroidal neovascularization (CNV) secondary to high myopia...
  15. Wang J, Ohno Matsui K, Yoshida T, Kojima A, Shimada N, Nakahama K, et al. Altered function of factor I caused by amyloid beta: implication for pathogenesis of age-related macular degeneration from Drusen. J Immunol. 2008;181:712-20 pubmed
    ..Our results showed that Abeta binds to complement factor I which inhibits the ability of factor I to cleave C3b to inactivated iC3b...
  16. Catterall C, Lyons A, Sim R, Day A, Harris T. Characterization of primary amino acid sequence of human complement control protein factor I from an analysis of cDNA clones. Biochem J. 1987;242:849-56 pubmed
  17. Kavanagh D, Richards A, Noris M, Hauhart R, Liszewski M, Karpman D, et al. Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome. Mol Immunol. 2008;45:95-105 pubmed
    ..The excessive complement activation for a given degree of damage may result in generation of a procoagulant state and aHUS. ..
  18. Moore I, Strain L, Pappworth I, Kavanagh D, Barlow P, Herbert A, et al. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood. 2010;115:379-87 pubmed publisher
    ..In 5 patients mutations were identified: 1 in CFH, 1 in CFI, 1 in CD46, and 2 in C3. The latter observation emphasizes that multiple concurrent factors may be necessary in individual patients for disease manifestation. ..
  19. Leitão M, Vilela M, Rutz R, Grumach A, Condino Neto A, Kirschfink M. Complement factor I deficiency in a family with recurrent infections. Immunopharmacology. 1997;38:207-13 pubmed
    ..3 of these obviously heterozygously deficient family members suffered from recurrent bacterial infections of different frequency and severity. ..
  20. Licht C, Fremeaux Bacchi V. Hereditary and acquired complement dysregulation in membranoproliferative glomerulonephritis. Thromb Haemost. 2009;101:271-8 pubmed
    ..A better understanding of the pathogenesis of MPGN is crucial for the development of novel, specific treatment strategies...
  21. Genel F, Sjöholm A, Skattum L, Truedsson L. Complement factor I deficiency associated with recurrent infections, vasculitis and immune complex glomerulonephritis. Scand J Infect Dis. 2005;37:615-618 pubmed
    Here we report complement factor I deficiency in an 11-y-old girl from a consanguineous Turkish family, who presented with recurrent pyogenic infections, vasculitic eruptions and immune complex glomerulonephritis...
  22. Nilsson S, Nita I, Månsson L, Groeneveld T, Trouw L, Villoutreix B, et al. Analysis of binding sites on complement factor I that are required for its activity. J Biol Chem. 2010;285:6235-45 pubmed publisher
    ..These same mutants also showed impaired binding to C3met. In conclusion, the FIMAC domain appears to harbor the main binding sites important for the ability of FI to degrade C4b and C3b. ..
  23. Kavanagh D, Pappworth I, Anderson H, Hayes C, Moore I, Hunze E, et al. Factor I autoantibodies in patients with atypical hemolytic uremic syndrome: disease-associated or an epiphenomenon?. Clin J Am Soc Nephrol. 2012;7:417-26 pubmed publisher
    ..These findings reinforce the concept of multiple concurrent risk factors being associated with atypical hemolytic uremic syndrome but question whether autoantibodies per se predispose to atypical hemolytic uremic syndrome. ..
  24. Ponce Castro I, González Rubio C, Delgado Cerviño E, Abarrategui Garrido C, Fontan G, Sanchez Corral P, et al. Molecular characterization of Complement Factor I deficiency in two Spanish families. Mol Immunol. 2008;45:2764-71 pubmed publisher
    b>Complement Factor I (CFI) is a regulator of the classical and alternative pathways. CFI has enzymatic activity and is able to cleave C3b and C4b. Homozygous Factor I deficiency is associated with infectious and/or autoimmune diseases...
  25. Chen W, Stambolian D, Edwards A, Branham K, Othman M, Jakobsdottir J, et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A. 2010;107:7401-6 pubmed publisher
    ..Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies. ..
  26. Okroj M, Hsu Y, Ajona D, Pio R, Blom A. Non-small cell lung cancer cells produce a functional set of complement factor I and its soluble cofactors. Mol Immunol. 2008;45:169-79 pubmed
  27. Le Quintrec M, Lionet A, Kamar N, Karras A, Barbier S, Buchler M, et al. Complement mutation-associated de novo thrombotic microangiopathy following kidney transplantation. Am J Transplant. 2008;8:1694-701 pubmed publisher
    ..These results suggest that genetic abnormalities may represent risk factors for de novo TMA after kidney transplantation and raise the question of the best therapeutic strategy. ..
  28. Chung K, Liszewski M, Nybakken G, Davis A, Townsend R, Fremont D, et al. West Nile virus nonstructural protein NS1 inhibits complement activation by binding the regulatory protein factor H. Proc Natl Acad Sci U S A. 2006;103:19111-6 pubmed publisher
    ..Accordingly, extracellular NS1 may function to minimize immune system targeting of West Nile virus by decreasing complement recognition of infected cells...
  29. González Rubio C, Ferreira Cerdán A, Ponce I, Arpa J, Fontan G, Lopez Trascasa M. Complement factor I deficiency associated with recurrent meningitis coinciding with menstruation. Arch Neurol. 2001;58:1923-8 pubmed
    ..First, we characterized the existence of a total complement factor I deficiency defined by undetectable levels by enzyme immunosorbent assay...
  30. Kunnath Muglia L, Chang G, Sim R, Day A, Ezekowitz R. Characterization of Xenopus laevis complement factor I structure--conservation of modular structure except for an unusual insert not present in human factor I. Mol Immunol. 1993;30:1249-56 pubmed
    ..The modular structure of the frog heavy chain was analyzed, and found to differ vis-à-vis previously published analyses of human factor I. We also evaluate the timing of factor I transcription during frog embryogenesis. ..
  31. Hair P, Ward M, Semmes O, Foster T, Cunnion K. Staphylococcus aureus clumping factor A binds to complement regulator factor I and increases factor I cleavage of C3b. J Infect Dis. 2008;198:125-33 pubmed publisher
    ..rClfA and the shed ClfA fragment increased factor I cleavage of C3b into inactive C3b. Our findings describe a new S. aureus mechanism for modification of host complement activities. ..
  32. Bexborn F, Andersson P, Chen H, Nilsson B, Ekdahl K. The tick-over theory revisited: formation and regulation of the soluble alternative complement C3 convertase (C3(H2O)Bb). Mol Immunol. 2008;45:2370-9 pubmed
    ..Under conditions that totally inactivated C3bBb, C3(H(2)O)Bb still retained approximately 25% of its initial activity. ..
  33. Cunnion K, Buescher E, Hair P. Serum complement factor I decreases Staphylococcus aureus phagocytosis. J Lab Clin Med. 2005;146:279-86 pubmed
    ..aureus surface, and thereby enhancing opsonophagocytosis, is a promising potential target for therapeutic intervention. ..
  34. Blom A, Kask L, Dahlback B. CCP1-4 of the C4b-binding protein alpha-chain are required for factor I mediated cleavage of complement factor C3b. Mol Immunol. 2003;39:547-56 pubmed
    ..However, in both cases 1,000-fold molar excess of C4BP over factor H (FH), well known inhibitor of the alternative pathway, was required to obtain the same effect. ..
  35. Terado T, Nonaka M, Nonaka M, Kimura H. Conservation of the modular structure of complement factor I through vertebrate evolution. Dev Comp Immunol. 2002;26:403-13 pubmed
    Mammalian complement factor I plays pivotal roles in the regulation of complement activation and generation of important biological activities from C3...
  36. Sadallah S, Gudat F, Laissue J, Spath P, Schifferli J. Glomerulonephritis in a patient with complement factor I deficiency. Am J Kidney Dis. 1999;33:1153-7 pubmed
    b>Complement factor I deficiency is known to be associated with recurrent pyogenic infections. The patient described here had recurrent attacks of otitis, sinusitis, and bronchopneumonia since childhood...
  37. Minta J, Fung M, Turner S, Eren R, Zemach L, Rits M, et al. Cloning and characterization of the promoter for the human complement factor I (C3b/C4b inactivator) gene. Gene. 1998;208:17-24 pubmed
    b>Complement factor I is a serine proteinase that regulates the classical and alternative pathways of complement by cleaving C3b and C4b and preventing the assembly of C3 and C5 convertase enzymes...
  38. Vyse T, Morley B, Bartok I, Theodoridis E, Davies K, Webster A, et al. The molecular basis of hereditary complement factor I deficiency. J Clin Invest. 1996;97:925-33 pubmed
    The molecular basis of hereditary complement factor I deficiency is described in two pedigrees...
  39. Fagerness J, Maller J, Neale B, Reynolds R, Daly M, Seddon J. Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet. 2009;17:100-4 pubmed publisher
    ..This analysis identified a single nucleotide polymorphism just 3' of complement factor I on chromosome 4 showing significant association (P<10(-7))...
  40. Nilsson S, Sim R, Lea S, Fremeaux Bacchi V, Blom A. Complement factor I in health and disease. Mol Immunol. 2011;48:1611-20 pubmed publisher
    ..FI cleaves its in vivo substrates C3b and C4b only in the presence of cofactors, it shows poor enzymatic activity towards synthetic substrates tested so far and it has no natural inhibitor. ..
  41. Botto M, Kirschfink M, Macor P, Pickering M, Wurzner R, Tedesco F. Complement in human diseases: Lessons from complement deficiencies. Mol Immunol. 2009;46:2774-83 pubmed publisher
  42. Smailhodzic D, Klaver C, Klevering B, Boon C, Groenewoud J, Kirchhof B, et al. Risk alleles in CFH and ARMS2 are independently associated with systemic complement activation in age-related macular degeneration. Ophthalmology. 2012;119:339-46 pubmed publisher
    ..Especially the C3d/C3 ratio seems to be a strong marker for AMD. The findings suggest that CFH and ARMS2 share a common pathway in the pathogenesis of AMD. ..
  43. Schlaf G, Demberg T, Koleva M, Jungermann K, Gotze O. Complement factor I is upregulated in rat hepatocytes by interleukin-6 but not by interferon-gamma, interleukin-1beta, or tumor necrosis factor-alpha. Biol Chem. 2001;382:1089-94 pubmed
    b>Complement factor I (FI) is a regulatory serine protease of the complement system which cleaves three peptide bonds in the alpha-chain of C3b and two bonds in the alpha-chain of C4b and thus prevents the assembly of the C3 and C5 ..
  44. Nakanishi I, Moutabarrik A, Hara T, Hatanaka M, Hayashi T, Syouji T, et al. Identification and characterization of membrane cofactor protein (CD46) in the human kidneys. Eur J Immunol. 1994;24:1529-35 pubmed
  45. Haerynck F, Stordeur P, Vandewalle J, Van Coster R, Bordon V, De Baets F, et al. Complete factor I deficiency due to dysfunctional factor I with recurrent aseptic meningo-encephalitis. J Clin Immunol. 2013;33:1293-301 pubmed publisher
    ..b>Complement factor I (FI), a serine protease, is an important regulator of alternative pathway activation...
  46. Lachmann P, Lay E, Seilly D, Buchberger A, Schwaeble W, Khadake J. Further studies of the down-regulation by Factor I of the C3b feedback cycle using endotoxin as a soluble activator and red cells as a source of CR1 on sera of different complotype. Clin Exp Immunol. 2016;183:150-6 pubmed publisher
    ..This may, however, reflect that the Cambridge BioResource volunteers do not include many very young or very elderly patients, and in general comprise a population not greatly at risk of death from infectious disease. ..
  47. Sullivan M, Erlic Z, Hoffmann M, Arbeiter K, Patzer L, Budde K, et al. Epidemiological approach to identifying genetic predispositions for atypical hemolytic uremic syndrome. Ann Hum Genet. 2010;74:17-26 pubmed publisher
    ..Occurrence of homo- and heterozygous mutations in the same gene suggests that the number of necessary DNA variants remains unclear. Among clinical information only familial occurrence predicts a mutation. ..
  48. Lambris J, Lao Z, Oglesby T, Atkinson J, Hack C, Becherer J. Dissection of CR1, factor H, membrane cofactor protein, and factor B binding and functional sites in the third complement component. J Immunol. 1996;156:4821-32 pubmed
  49. Timár K, Pasch M, van den Bosch N, Jarva H, Junnikkala S, Meri S, et al. Human keratinocytes produce the complement inhibitor factor H: synthesis is regulated by interferon-gamma. Mol Immunol. 2006;43:317-25 pubmed
    ..Factor H released in response to IFN-gamma was functionally active. In conclusion, we demonstrate that keratinocytes are capable of synthesizing factor H and that this synthesis is regulated by IFN-gamma. ..
  50. Rose K, Paixao Cavalcante D, Fish J, Manderson A, Malik T, Bygrave A, et al. Factor I is required for the development of membranoproliferative glomerulonephritis in factor H-deficient mice. J Clin Invest. 2008;118:608-18 pubmed publisher
  51. Wu Y, Qu H, Sfyroera G, Tzekou A, Kay B, Nilsson B, et al. Protection of nonself surfaces from complement attack by factor H-binding peptides: implications for therapeutic medicine. J Immunol. 2011;186:4269-77 pubmed publisher
    ..Our study therefore provides a promising and novel approach to produce therapeutic materials with enhanced biocompatibility. ..
  52. van de Ven J, Nilsson S, Tan P, Buitendijk G, Ristau T, Mohlin F, et al. A functional variant in the CFI gene confers a high risk of age-related macular degeneration. Nat Genet. 2013;45:813-7 pubmed publisher
    ..Taken together, these findings demonstrate that rare, highly penetrant mutations contribute to the genetic burden of AMD...
  53. Del Tordello E, Vacca I, Ram S, Rappuoli R, Serruto D. Neisseria meningitidis NalP cleaves human complement C3, facilitating degradation of C3b and survival in human serum. Proc Natl Acad Sci U S A. 2014;111:427-32 pubmed publisher
    ..We conclude that NalP is an important factor to increase the survival of Nm in human serum. ..